Calcium is the major element in bones. Over 99% of the body's calcium resides in bones. Approximately 80-90% of bone mineral content is comprised of calcium and phosphorus. Adequate intake of calcium from diet is necessary for bone growth and maintenance. Osteoporosis is a disease caused by a significant loss of bone mass which leads to increased susceptibility to fracture. This condition often occurs in women age 35 or above. More frequently, it occurs in postmenopausal women (Ilich and Kerstetter, 2000; Ilich et al., 2003).
Dietary supplement with calcium was thought to be the prime factor in the maintenance of bone health in the past 50 years (Seelig et al., 2004). However, the benefit of increased calcium consumption has not been clearly demonstrated for bone health. Instead, high calcium intake may be linked to higher incidence of cardiovascular disease (Seelig et al., 2004). Increased risk of cardiovascular disease was also attributed to a continued increase in calcium to magnesium ratio (Ca/Mg) in the diet. The ratio of Ca/Mg increased from 2/1 in the first 40 years of the 1900 to >3/1 in the sixties, to >6/1 in 2000. The daily recommended intake (DRI) in 2000 was >3/1 to >4/1.
There are conflicting reports in the literature concerning the importance of dietary calcium on bone health. Heaney (1993b; Heaney, 1993a) reviewed 43 studies of calcium published between 1988 and 1993. Although 16 studies showed that calcium had no effect on bone loss, 16 of the 19 placebo-controlled studies in which calcium intake was controlled did show that the mineral prevented or slowed bone loss.
In the 12 studies that excluded women who were within 5 years of menopause, a period when estrogen deficiency overwhelms the effect of calcium supplementation (Riis et al., 1987), all showed that calcium had a significant beneficial effect.
In elderly women, it was shown that there was a significant relationship between bone mineral density (BMD) and several critical nutrients: energy, protein, calcium, magnesium, zinc and vitamin C (Ilich et al., 2003).
In the early 2000, daily calcium intake reached a new high of 2,500 mg (Seelig et al., 2004). It should be noted that the increase in Ca/Mg is mainly due to the increase in calcium intake, not a change in magnesium. The daily requirement of calcium was recently re-evaluated (Hunt and Johnson, 2007). It was found that an average intake of 749 mg of calcium is required, an estimate lower than previously estimated.
In one clinical trial, 43 early postmenopausal women were randomly assigned to one of the treatment groups: percutaneous estradiol, oral calcium (2000 mg/day) or placebo. Bone mineral content in the forearm, the entire body and spine remained the same in the estradiol group; however, there was a decline in the calcium and placebo groups. Calcium did not show any significant effect and calcium supplementation may have a minor effect on the loss of cortical bone, but it had no effect on the trabecular bone (Riis et al., 1987).
In a National Health and Nutritional Examination Survey (NHANES) conducted from 1988 to 1994, predictive models were established to evaluate parameters such as race, body composition, exercise, alcohol intake, smoking status and nutritional intake (Bass et al., 2006). Nutritional intake includes elements such as calcium, phosphorus, magnesium, iron, zinc, sodium and potassium. Among the 7,532 women, 20 years or older, elemental intake was not a predictor of osteoporosis. This observation may not be surprising because the average calcium intake was 659 mg and magnesium was 241 mg. These values were lower than that of RDA of 1000 and 310 mg, respectively.
Physical activity was associated with increase in vertebral bone mineral density (Kanders et al., 1988). When activity was removed, vertebral bone mineral density was dependent on calcium intake. The relationship disappeared when calcium intake exceeded 800 to 1000 mg/day. A ceiling effect of calcium was also observed by Celotti and Bignamini (1999). They reported that calcium supplementation is important for maintaining bone health. However, an excessive amount of calcium may be useless and could cause hypercalciuria and kidney stones. Supplementation with a small amount of magnesium was suggested.
Mutlu et al. (2007) showed that magnesium and zinc levels are the lowest in postmenopausal women, lower than postmenopausal women with osteopenia, and lower than postmenopausal women with normal bone density. Calcium supplementation may reduce zinc absorption, and magnesium and zinc retention. These conditions further aggravate the severity of osteoporosis (Ilich and Kerstetter, 2000; Lowe et al., 2002; Abrams and Atkinson, 2003). Besides calcium, magnesium, zinc, manganese and copper deficiencies are linked to osteoporosis (Saltman and Strause, 1993).
Angus et al. (1988b) showed that calcium was not a predictor of bone mineral density in pre- and post-menopausal women. Magnesium and iron are predictors of bone mineral density. In this study, about 29% of the post-menopausal women consumed less than 500 mg of calcium per day (Angus et al., 1988a). Other nutrients such as magnesium, etc. are also deficient.
A study emphasizing the benefit of magnesium on postmenopausal women found that a Mg/Ca ratio of 1.2/1 was more effective than that of a ratio of 0.4/1 (Abraham and Grewal, 1990). The study used 500 mg of calcium in the form of calcium citrate and 200 mg of magnesium in the form of magnesium oxide for the 0.4/1 group and 600 mg of magnesium in the form of magnesium oxide in the 1.2/1 group. The study showed that women on the 1.2/1 diet for 6 to 12 months had an average of 11% increase in bone mineral density, whereas, the other group had a non-significant increase of 0.7%.
Magnesium supplementation (250 mg/day) in young women has been shown to have no effects on calcium resorption (Basso et al., 2000). This study was a short term study. Therefore, the validity of the results is yet to be confirmed.
Ilich (2000) wrote, “Osteoporosis is a complex, multi-factorial condition characterized by reduced bone mass and impaired micro-architectural structure, leading to an increased susceptibility to fractures. Although most of the bone strength (including bone mass and quality) is genetically determined, many other factors (nutritional, environmental and life-style) also influence bone. Nutrition is an important modifiable factor in the development and maintenance of bone mass and the prevention and treatment of osteoporosis. Approximately 80-90% of bone mineral content is comprised of calcium and phosphorus. Other dietary components, such as protein, magnesium, zinc, copper, iron, fluoride, vitamins D, A, C, and K are required for normal bone metabolism, while other ingested compounds not usually categorized as nutrients (e.g. caffeine, alcohol, phytoestrogens) may also impact on bone health. Unraveling the interaction between different factors; nutritional, environmental, life style, and heredity help us to understand the complexity of the development of osteoporosis and subsequent fractures. This paper reviews the role of dietary components on bone health throughout different stages of life. Each nutrient is discussed separately; however the fact that many nutrients are co-dependent and simultaneously interact with genetic and environmental factors should not be neglected. The complexity of the interactions is probably the reason why there are controversial or inconsistent findings regarding the contribution of a single or a group of nutrients in bone health.”
Although bone health is dependent on a variety of factors, there is enough evidence to show that, in the area of elemental requirements, apart from calcium, other elements such as magnesium, phosphorus, zinc, copper, etc. are also important for maintaining or improving bone health.
Despite the values cited in the Recommended Daily Allowance (RDA), Allowable Intake (AI) or Recommended Daily Intake (RDI) for elemental intake, there was not much attention paid to the form of elements consumed. It is not clear whether calcium salts can be used interchangeably. It is understandable that not all calcium salts are created alike; there are differences in solubility and absorption. If there are differences in bioavailability, shouldn't elemental salts be more accurately characterized in terms of absorbability?
These issues have not received appropriate attention because there are reports showing solubility of calcium salts is not related to the element's bioavailability. The absorption of calcium salt, soluble or insoluble, is not affected by gastric acid secretion (Bo-Linn et al., 1984). The hypothesis that calcium carbonate can be converted to a more soluble calcium salt, calcium chloride in the stomach, which enhances calcium absorption has been tested. The results showed that calcium carbonate absorption is not influenced by gastric acid (Bo-Linn et al., 1984). The amount absorbed in humans is 24%.
The bioavailability of calcium carbonate, D-calcium lactate, L-calcium lactate and oyster shell calcium was found to be independent of the salt's solubility (Tsugawa et al., 1995). This study used a method which was different from that of the balance study. It measured changes in the pituitary thyroid hormone (PTH), etc. instead of actual calcium absorption. Accurate comparison of calcium bioavailability cannot be achieved using an indirect method such as PTH.
Heaney (2001) reported that rates of urinary excretion for three marketed calcium products (marketed calcium carbonate, encapsulated calcium carbonate and marketed calcium citrate) were identical. Using Ca45 as a tracer, fractional absorption values of calcium carbonate and calcium citrate were found to be insignificantly different from each other at a low dose (300 mg calcium); however, calcium absorption from calcium carbonate was slightly but significantly better than calcium citrate (Heaney et al., 1999).
Magnesium absorption from 10 organic and inorganic salts was tested in rats (Coudray et al., 2005). The bioavailability of magnesium ranged from 50 to 66%. Magnesium gluconate provided the highest value. Solubility of these salts in the small and large intestine and cecum was measured. Solubility of these salts is actually quite high at the proximal section of the intestine; it dropped off very quickly as pH increase along the intestinal tract. Differences in absorption of these magnesium salts may not be important considering the variability among individuals.
Bioavailability of elements in fortified foods has been measured using dual isotope techniques (Abrams et al., 2002). There was no difference in the bioavailability of zinc oxide and zinc sulfate; both are at approximately 24%. The bioavailability of iron was 15.9%. However, zinc sulfate tended to reduce the bioavailability of iron to 11.5% and this number is significant. The absorption of calcium in fortified cereal was 28.9%; in unfortified cereal was 30.8%.
Despite these observations, there are reports showing that not all calcium salts have the same bioavailability.
Bioavailability of calcium ascorbate is higher than that of calcium carbonate and calcium chloride (Tsugawa et al., 1999). The bioavailability was measured using 45Ca. Solubility of these salts under different pH conditions was also measured.
Bioavailability of calcium acetate was measured using 45Ca (Cai et al., 2004). Compared to calcium ascorbate, bioavailability of calcium acetate was significantly lower (70% vs 45% at 25 mg calcium load). A kinetic model consisting of 8 compartments was used to fit the plasma calcium vs. time data. The difference was attributed to a saturable process. It is also reasoned that the solubility of calcium acetate may be reduced in the intestine because calcium from the acetate salt may precipitate phosphate or chloride ions in the intestine.
Therefore, it is not surprising that the bioavailability of calcium acetate is not different from that of calcium chloride and calcium phosphate.
Ten mg of zinc per day is the recommended intake (Record et al., 1985). The recommended daily allowance of zinc was 6 mg (Smith et al., 1983). The authors warned that recommended daily allowance should not be confused with that of recommended daily intake.
Zinc absorption occurs throughout the small intestine and it is dose dependent in humans (Lee et al., 1989).
A patent was filed in 1999 for a calcium dietary supplement comprising calcium, magnesium, zinc, etc. (Ellenbogen and Buono, 1999). The calcium to magnesium ratio is really high and the range of magnesium used was between 50 to 150 mg. The salt for calcium is calcium carbonate. The quantity of calcium and magnesium used and the type of salts employed are different from the present invention.
Meigant and Stenger (2004) filed a U.S. patent citing the a composition which consists of calcium and a vitamin D mixture. It is mentioned that synergism was involved. The thrust of the present application shares no common ground with the application of Meigant and Stenger (2004).
Hendricks (2004) was awarded a patent on a dietary supplement containing calcium and phosphorus. Vitamins including vitamin D could also be included in the supplement. Hendricks emphasized the effects of phosphorus, and perhaps vitamins. The present application, however, does not include phosphorus.
Mazer et al. (1997) was granted a patent on a calcium supplement in solid form which contains calcium glycerophosphate, vitamin D and vitamin C. Again, the present invention does not contain calcium salt of this kind.
In another patent, the synthesis of dicalcium citrate-lactate was described by mixing stoichiometric mixtures of citrate and lactate salts to produce the calcium salt (Walsdorf et al., 1991).
Krumhar and Johnson (2006) designed a diet supplement for bone health consisting of microcrystalline calcium hydroxyapatite, protein (mostly collagen), phosphorus, fat, and other minerals. It also contains vitamin D3, cholecalciferol, and a preferred osteoblast stimulant, ipriflavone. In addition to these basic ingredients, the composition can further include various other minerals known to occur in bone, vitamin C, and glucosamine sulfate, all of which have been claimed to have beneficial effects on the growth and maintenance of healthy bone. A method for benefiting human bone health involves administering a daily regimen of the dietary supplement.
There is another daily vitamin and mineral supplement for women comprising vitamin A, beta-carotene, niacin, riboflavin, pantothenic acid, pyridoxine, cyanocobalamin, biotin, para-aminobenzoic acid, inositol, choline, vitamin C, vitamin D, vitamin E, vitamin K, boron, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, selenium, zinc and bioflavonoid. For women up to 40 years of age, iron is included. For women over 40 years of age, iron is optionally included (Sultenfuss, 1996). Ca/Mg ratio is 1000-1500/400-600.
A dietary supplement consisting of an extensive list of minerals and vitamins was described in a patent (Jackson and Blumberg, 1997). There is no quantitative description on the contribution of each component to bone health. The focus of this prior patent is distinctly different from the present invention.
Much attention has been focused on calcium as the element for bone health. However, not all calciums are the same and their relative bioavailability determines the fractional amount that reaches the systemic circulation. As for maintenance of bone health, other essential elements are required. There are hints in the literature suggesting that potential interactions between these elements exist. The impact on absorption, calcium utilization and consequently, bone health has not been systematically investigated. Furthermore, vitamins such as D3 and K2 have been implicated in calcium absorption and increase in bone mineral density (BMD); however, the interplay between bioavailable elements, such as calcium, magnesium and zinc, with vitamins has not been illustrated. The complicated environment in the gastrointestinal tract plays a dominant role in determining the absorbability of elements. In particular, cations and anions may play a significant role in altering the solubility of an elemental salt in the gastrointestinal tract (GIT). The importance of these factors in determining the bioavailability of elements has never been thoroughly addressed. In this invention, a calcium supplement, comprising optimum amounts of acetate salts of calcium, magnesium and zinc, and vitamin D3, is described. The daily dosage of calcium is significantly lower than that of regular calcium supplement. This product was designed using in vitro and in vivo models which are key to determining elemental balance.